Regulation of bone homeostasis by controlling osteoclasts and osteoblasts

• Project/Area Number: 24390359
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: MIYAMOTO Takeshi 慶應義塾大学, 医学部, 講師 (70383768)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2012: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 骨代謝 / 破骨細胞 / 骨芽細胞 / 骨粗鬆症 / Blimpl / 分化 / 骨

Outline of Final Research Achievements

Bone homeostasis is regulated in a delicate balance between bone resorbing osteoclasts and bone forming osteoblasts. In this study, we found that B lymphocyte induced maturation protein 1 (Blimp1) plays a crucial role in regulating osteoclastogenesis and bone mass at an adult stage, and targeting Blimp1 in adult mice resulted in significant inhibition of osteoclast formation followed by increased bone mass. We also found that osteoclast stimulatory transmembrane protein (OC-STAMP) is required for osteoclast cell-cell fusion, and OC-STAMP-deficient mice exhibited complete abrogation of osteoclast cell-cell fusion. We further found that B cell lymphoma 6 (Bcl6) plays a role in regulating osteoblastogenesis via suppressing expression of signal transducer and activator of transcription 1 (Stat1), and Bcl6-deificient osteoblasts showed altered differentiation owing to Stat1 elevation. Bcl6/Stat1 doubly deficient mice exhibited reversed osteoblastogenesis compared with Bcl6-deficient mice.

Research Products

• [Journal Article] Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells. (2015)
  • Author(s): Katsuyama E, Miyamoto H, Kobayashi T, Sato Y, Hao W, Kanagawa H, Fujie A, Tando T, Watanabe R, Morita M, Miyamoto K, Niki Y, Morioka H, Matsumoto M, Toyama Y, Miyamoto T.
  • Journal Title: J Biol Chem. Volume: 290 Pages: 716-726
  • DOI: 10.1074/jbc.m114.568360
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mycobacterium tuberculosis promotes arthritis development through toll-like receptor 2. (2015)
  • Author(s): Kanagawa H, Niki Y, Kobayashi T, Sato Y, Katsuyama E, Fujie A, Hao W, Miyamoto K, Tando T, Watanabe R, Morita M, Morioka H, Matsumoto M, Toyama Y, Miyamoto T.
  • Journal Title: J Bone Miner Metab. Volume: 33 Pages: 135-141
  • DOI: 10.1007/s00774-014-0575-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Bcl6 promotes osteoblastogenesis through Stat1 inhibition. (2015)
  • Author(s): Fujie A, Funayama A, Miyauchi Y, Sato Y, Kobayashi T, Kanagawa H, Katsuyama E, Hao W, Tando T, Watanabe R, Morita M, Miyamoto K, Kanaji A, Morioka H, Matsumoto M, Toyama Y and Miyamoto T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 457 Pages: 451-456
  • DOI: 10.1016/j.bbrc.2015.01.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state (2014)
  • Author(s): Mori T
  • Journal Title: Oncogene Volume: Epub ahead of print Pages: 4236-4241
  • DOI: 10.1038/onc.2013.545
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The Vitamin D Analogue ED71 but Not 1,25(OH)2D3 Targets HIF1α Protein in Osteoclasts. (2014)
  • Author(s): Sato Y, Miyauchi Y, Yoshida S, Morita M, Kobayashi T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Tando T, Watanabe R, Miyamoto K, Morioka H, Matsumoto M, Toyama Y, Miyamoto T.
  • Journal Title: PLoS One Volume: 9
  • DOI: 10.1371/journal.pone.0111845
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] HIF1 α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis (2013)
  • Author(s): Miyauchi Y, Sato Y, Kobayashi T, Yoshida S, Mori T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Miyamoto K, Tando T, Morioka H, Matsumoto M, Chambon P, Johnson RS, Kato S, Toyama Y, Miyamoto T.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 110 Pages: 16568-16573
  • DOI: 10.1073/pnas.1308755110
  • Peer Reviewed
• [Journal Article] STATs and macrophage fusion. (2013)
  • Author(s): Miyamoto T.
  • Journal Title: JAKSTAT Volume: 2
  • Peer Reviewed
• [Journal Article] Role of osteoclasts in regulating hematopoietic stem and progenitor cells. (2013)
  • Author(s): Miyamoto T.
  • Journal Title: World J Orthop. Volume: 4 Pages: 198-206
  • Peer Reviewed
• [Journal Article] IL-32-PAR2 axis is an innate immunity sensor providing alternative signaling for LPS-TRIF axis (2013)
  • Author(s): Nakayama M, Niki Y, Kawasaki T, Takeda Y, Ikegami H, Toyama Y, Miyamoto T.
  • Journal Title: Scientific Reports Volume: 3 Pages: 2960-2960
  • DOI: 10.1038/srep02960
  • Peer Reviewed
• [Journal Article] Twist2 functions as a tumor suppressor in murine osteosarcoma cells (2013)
  • Author(s): Ishikawa T, Shimizu T, Ueki A, Yamaguchi S, Onishi N, Sugihara E, Kuninaka S, Miyamoto T, Morioka H, Nakayama R, Kobayashi E, Toyama Y, Mabuchi Y, Matsuzaki Y, Yamaguchi R, Miyano S and Saya H
  • Journal Title: Cancer Science Volume: (in press) Pages: 880-8
  • DOI: 10.1111/cas.12163
  • Peer Reviewed
• [Journal Article] An essential role for STAT6-STAT1 protein signaling in promoting macrophage cell-cell fusion (2012)
  • Author(s): Miyamoto H, et al.
  • Journal Title: J Biol Chem. Volume: 287 Pages: 32479-84
  • Peer Reviewed
• [Journal Article] Conditional inactivation of Blimp1 in adult mice promotes increased bone mass. (2012)
  • Author(s): Miyauchi Y, Miyamoto H, Yoshida S, Mori T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Hoshi H, Miyamoto K, Sato Y, Kobayashi T, Akiyama H, Morioka H, Matsumoto M, Toyama Y, Miyamoto T
  • Journal Title: Journal of Biological Chemistry. Volume: vol. 287 Pages: 28508-17
  • DOI: 10.1074/jbc.m112.356634
  • Peer Reviewed
• [Journal Article] Enhanced susceptibility to 1 ipopolysaccharide-induced arthritis and end otoxin shock in interleukin-32 alpha transgenic mice through induction of tumor necrosis factor alpha (2012)
  • Author(s): Nakayama M., Niki Y., Kawasaki T., Takeda Y., Horiuchi K., Sasaki A., Okada Y., Umezawa K., Ikegami H., Toyama Y. and Miyamoto T.
  • Journal Title: Arthritis Research and Therapy Volume: 14
  • DOI: 10.1186/ar3850
  • Peer Reviewed
• [Journal Article] Clinical Significance of Cartilage Biomarkers for Monitoring Structural Joint Damage in Rheumatoid Arthritis Patients Treated with Anti-T NF Therapy (2012)
  • Author(s): Niki Y, et al.
  • Journal Title: PLoS One Volume: 7
  • DOI: 10.1371/journal.pone.0037447
  • Peer Reviewed
• [Journal Article] PDGFBB promotes PDGFRa-positive cell migration into artificial bone in vivo (2012)
  • Author(s): Yoshida S, Iwasaki R, Kawana H, Miyauchi Y, Hoshi H, Miyamoto H, Mori T, Kanagawa H et al.
  • Journal Title: Biochem Biophys Res Commun Volume: 421 Pages: 785-789
  • DOI: 10.1016/j.bbrc.2012.04.084
  • Peer Reviewed
• [Journal Article] Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis. (2012)
  • Author(s): Hoshi H, Hao W, Fujita Y, Funayama A, Miyauchi Y, Hashimoto K, Miyamoto K, (他21名)
  • Journal Title: Journal of Bone and Mineral Research. Volume: 27(9) Pages: 2015-2023
  • DOI: 10.1002/jbmr.1634
  • Peer Reviewed
• [Journal Article] Serum cartilage metabolites as biomarkers of degenerative lumbar scoliosis. (2012)
  • Author(s): Hosogane N, et al
  • Journal Title: J. Orthop. Res Volume: (In press) Pages: 1249-53
  • DOI: 10.1002/jor.22067
  • Peer Reviewed
• [Journal Article] Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells. (2012)
  • Author(s): Miyamoto H, et al
  • Journal Title: Journal of Bone and Mineral Research. Volume: (In press) Pages: 1289-1297
  • DOI: 10.1002/jbmr.1575
  • Peer Reviewed
• [Presentation] TNFα and IL-1 promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state (2014)
  • Author(s): Takeshi Miyamoto
  • Organizer: Cold Spring Harbor, Asia Bone and Cartilage
  • Place of Presentation: Suzhou, China
  • Year and Date: 2014-11-03 – 2014-11-07
  • Invited
• [Presentation] 骨代謝の理解と骨粗鬆症治療 (2014)
  • Author(s): 宮本健史
  • Organizer: 第１６回日本骨粗鬆症学会
  • Place of Presentation: 新宿
  • Year and Date: 2014-10-23 – 2014-10-25
  • Invited
• [Presentation] 臨床応用を見据えた骨代謝研究 (2014)
  • Author(s): 宮本健史
  • Organizer: 第２９回日本整形外科学会基礎学術総会
  • Place of Presentation: 鹿児島
  • Year and Date: 2014-10-08 – 2014-10-10
  • Invited
• [Presentation] Transcriptional Regulation of Osteoclastogenesis (2014)
  • Author(s): Takeshi Miyamoto
  • Organizer: 5th International Conference on Osteoimmunology
  • Place of Presentation: Kos, Greece
  • Year and Date: 2014-06-15 – 2014-06-18
  • Invited
• [Presentation] RANKLを標的とした新しい骨粗鬆症治療～骨代謝の理解に基づく骨粗鬆症治療～ (2014)
  • Author(s): 宮本健史
  • Organizer: 第８７回日本整形外科学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2014-05-22 – 2014-05-25
  • Invited
• [Presentation] 骨粗鬆症をめぐる最新の基礎研究 (2014)
  • Author(s): 宮本健史
  • Organizer: 第５８回日本リウマチ学会総会・学術集会
  • Place of Presentation: 高輪
  • Year and Date: 2014-04-24 – 2014-04-26
  • Invited
• [Presentation] Regulation of haematopoietic stem cells and progenitors by osteoclasts. (2013)
  • Author(s): Miyamoto T
  • Organizer: 1. Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Makuhari
• [Presentation] STAT6によるSTAT1の阻害がマクロファージの融合に必須である (2013)
  • Author(s): 勝山 詠理、宮本 健史、二木 康夫、戸山 芳昭
  • Organizer: 第２８回日本整形外科学会基礎学術集会
  • Place of Presentation: 幕張
• [Presentation] 金川裕矢、戸山芳昭、宮本健史 (2013)
  • Author(s): ヒトIL-1α conditional transgenicマウスはヒト自己炎症性症候群を反映する
  • Organizer: 第２８回日本整形外科学会基礎学術集会
  • Place of Presentation: 幕張
• [Presentation] TNFとIL-1は骨肉腫細胞株AXの腫瘍形成に必須のサイトカインである (2013)
  • Author(s): 森智章、森岡秀夫、戸山芳昭、宮本健史
  • Organizer: 第２８回日本整形外科学会基礎学術集会
  • Place of Presentation: 幕張
• [Presentation] 骨恒常性制御の分子機序 (2013)
  • Author(s): 宮本健史
  • Organizer: 第３１回日本骨代謝学会学術総会
  • Place of Presentation: 神戸国際会議場
• [Presentation] インターロイキン32aはToll様受容体シグナルを介してサイトカインを誘導し関節炎の病態に関与する (2012)
  • Author(s): 中山政憲, 他
  • Organizer: 第27回日本整形外科学会基礎学術集会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] in vivoにおいてPDGFBBはPRGFRa陽性細胞の遊走を促進させる (2012)
  • Author(s): 吉田重之, 他
  • Organizer: 第57回(公社)日本口腔外科学会総会・学術大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] PDGFBB Promotes PDGFR Alpha-positive Cell Migration into Artificial Bone in vivo (2012)
  • Author(s): Yoshida S, et al.
  • Organizer: Annual Meeting of the American Society for Bone and Mineral Research 2012
  • Place of Presentation: Minneapolis Convention Center
• [Presentation] ヒト2型糖尿病における骨梁微細構造の解析 (2012)
  • Author(s): 松崎健一郎, 他
  • Organizer: 第30回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場
• [Presentation] PDGF-BBは人工骨の生体親和性を上昇させる (2012)
  • Author(s): 吉田重之, 他
  • Organizer: 第30回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場
• [Presentation] 破骨細胞と骨恒常性制御 (2012)
  • Author(s): 宮本健史
  • Organizer: 第12回抗加齢医学会総会
  • Place of Presentation: パシフィコ横浜(招待講演)
• [Presentation] RANKLによる新しい破骨細胞の分子機能評価 (2012)
  • Author(s): 宮本健史
  • Organizer: 第85回日本整形外科学会
  • Place of Presentation: グランドプリンスホテル京都(招待講演)
• [Presentation] 整形外科の立場から見たBRONJの病態 (2012)
  • Author(s): 宮本健史
  • Organizer: 第23回日本臨床口腔病理学会 総会・学術集会
  • Place of Presentation: 東京医科歯科大学(招待講演)
  • Year and Date: 2012-08-30
• [Presentation] PDGFBB Promotes PDGFR Alpha-positive Cell Migration into Artificial Bone in vivo (2012)
  • Author(s): Yoshida S, et al.
  • Organizer: ASBMR Topical Meeting on Bone and Skeletal Muscle Interactions
  • Place of Presentation: Westein Kansas City at Crown Center
  • Year and Date: 2012-07-16